The effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea‐pig ventricular myocytes

Guerra, Laura; Cerbai, Elisabetta; Gessi, Stefania; Borea, Pier Andrea; Mugelli, Alessandro

doi:10.1111/j.1476-5381.1996.tb15534.x

Cited by 56 publications

(47 citation statements)

References 48 publications

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“…Lipid peroxidation alters membrane function by modifying phospholipid pools or by altering membrane-bound enzymes (33,35,37,38). Free radical-induced peroxidation of AA (45)(46)(47) results in formation of isoprostanes, which are stable prostaglandin-like compounds that are formed enzymatically (53) and nonenzymatically in vivo.…”

Section: Discussionmentioning

confidence: 99%

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Cheng¹,

Cao²,

Behar³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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1293-1304, 1997.). LES circular muscle strips were examined in muscle chambers as previously described (Biancani P, Billett G, Hillemeier C, Nissenshon M, Rhim BY, Sweczack S, and Behar J. Gastroenterology 103: 1199 -1206, 1992). Levels of inflammatory mediators were measured. IL-1␤ levels were higher in esophagitis than in normal LES. IL-1␤ reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H2O2. This was confirmed by IL-1␤-induced production of H2O2 in normal LES and elevated H2O2 levels in esophagitis. H2O2 by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H2O2 increased PGE2 in normal LES, and PGE2 levels were elevated in esophagitis LES, whereas PGF2␣ levels were unchanged. H2O2 also increased levels of 8-isoprostanes, stable prostaglandin-like compounds formed by free radical-induced peroxidation of arachidonic acid, and 8-isoprostane levels were elevated in esophagitis. The PGF2␣ analog 8-iso-PGF2␣ caused little contraction of LES strips but reduced PGF2␣ binding and contraction of normal LES. In esophagitis, PGF2␣ binding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1␤ causes production of H2O2. H2O2 increases PGE2, which relaxes the LES, and 8-iso-F2␣, which blocks PGF2␣-mediated contraction. smooth muscle; contraction; tone; signal transduction; hydrogen peroxide; cytokines; lower esophageal sphincter DISORDERS OF ESOPHAGEAL MOTOR function and lower esophageal sphincter (LES) competence affect more than one in ten adults over 40 years of age and one in four adults over 60. Gastroesophageal reflux disease (GERD) is by far the most common esophageal disorder. GERD may lead to the development of serious complications, including ulcers, strictures, bleeding, columnar metaplasia (Barrett's esophagus), and eventually adenocarcinoma of the esophagus.

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Section: Discussionmentioning

confidence: 99%

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Cheng¹,

Cao²,

Behar³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…General membrane damage secondary to ROS-mediated lipid peroxidation is one mechanism by which this can occur; however, more specific ROS-mediated effects also contribute. ROS can target L-type calcium channels on the sarcolemma and suppress the Ca 2+ current (82). ROS depress the activity of the sarcoplasmic reticulum Ca 2+ ATPase SERCA2, a membrane calcium pump that has been shown to play a crucial role in cardiac calcium handling and as a determinant of myocardial contractility (83).…”

Section: Ros Effects On Ion Channels and Calcium Fluxmentioning

confidence: 99%

Oxygen, oxidative stress, hypoxia, and heart failure

Giordano¹

2005

J. Clin. Invest.

1,173

733

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A constant supply of oxygen is indispensable for cardiac viability and function. However, the role of oxygen and oxygen-associated processes in the heart is complex, and they and can be either beneficial or contribute to cardiac dysfunction and death. As oxygen is a major determinant of cardiac gene expression, and a critical participant in the formation of ROS and numerous other cellular processes, consideration of its role in the heart is essential in understanding the pathogenesis of cardiac dysfunction.The mammalian heart is an obligate aerobic organ. At a resting pulse rate, the heart consumes approximately 8-15 ml O 2 /min/100 g tissue. This is significantly more than that consumed by the brain (approximately 3 ml O 2 /min/100 g tissue) and can increase to more than 70 ml O 2 /min/100 g myocardial tissue during vigorous exercise (1, 2). Mammalian heart muscle cannot produce enough energy under anaerobic conditions to maintain essential cellular processes; thus, a constant supply of oxygen is indispensable to sustain cardiac function and viability. The story of oxygen in the heart is complex, however, and goes well beyond its role in energy metabolism.Oxygen is a major determinant of myocardial gene expression, and as myocardial O 2 levels decrease, either during isolated hypoxia or ischemia-associated hypoxia, gene expression patterns in the heart are significantly altered (3). Oxygen participates in the generation of NO, which plays a critical role in determining vascular tone, cardiac contractility, and a variety of additional parameters. Oxygen is also central in the generation of reactive oxygen species (ROS), which can participate as benevolent molecules in cell signaling processes or can induce irreversible cellular damage and death. Oxygen is thus both vital and deleterious (4). The role of oxygen in myocardial energetics and metabolismThe heart can utilize a variety of metabolic fuels, including fatty acids, glucose, lactate, ketones, and amino acids. In the fed state, fatty acids are the preferred fuel, accounting for up to 90% of the total acetyl-CoA provided to cardiac mitochondria (5). Fatty acids are metabolized by β-oxidation, producing acetyl-CoA, NADH, and FADH 2 . The acetyl-CoA enters the Krebs cycle, producing more NADH and FADH 2 . Glucose is metabolized initially via the glycolytic pathway, producing a relatively small amount of ATP and also pyruvate, which enters the Krebs cycle, producing NADH and FADH 2 . In the absence of oxygen, the total amount of energy produced by these processes is insufficient to meet cardiac needs. The cardiac energy requirement is met, however, by entry of the resultant NADH and FADH 2 into the electron transport chain, which generates ATP by oxidative phosphorylation in the mitochondria. Oxygen serves as the terminal electron acceptor in the electron transport chain, and in the absence of sufficient oxygen, electron transport ceases and cardiac energy demands are not met (Figure 1). Generation and counterbalancing of ROSROS can be formed in the heart by a ...

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“…Key elements in cardiac excitation-contraction coupling are documented to be sensitive to oxidative stress. These include the L-type calcium channel, 30 the ryanodine receptor (calcium-release channel in the sarcoplasmic reticulum), 31 and the Ca 2ϩ -ATPase in the sarcoplasmic reticulum (SERCA2a). 32 This study does not delineate which of these targets is/are most protected by ascorbate treatment or which reactive oxygen or nitrogen species are involved in these events.…”

Section: Carnes Et Al Oxidative Stress and Atrial Electrical Remodelimentioning

confidence: 99%

Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation

Carnes

Chung

Nakayama

et al. 2001

Circulation Research

452

344

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Abstract-Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min Ϫ1) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation attenuated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2001;89:e32-e38.) Key Words: atrial fibrillation Ⅲ antioxidant Ⅲ ascorbate Ⅲ oxidative stress Ⅲ cardiac surgery A trial fibrillation (AF) is self-perpetuating 1 because of the combined effects of rate-induced electrophysiological and structural remodeling. 2 The earliest observed change in AF is an abbreviation of the atrial effective refractory period (ERP). The mechanisms by which high-rate activity results in electrophysiological remodeling are poorly understood. AF is also a frequent postoperative complication of cardiac surgery, with a reported incidence of 20% to 50%, increasing the risk of stroke. 3 Before arrhythmia onset, patients who experience postoperative AF exhibit increased atrial ectopy, abbreviation of monophasic action potential duration, and increased heart rate. 4 Evidence from animal models of atrial fibrillation, 5-7 as well as our studies of patients with postoperative AF, 8 supports a prominent role for myocyte calcium overload in initiating the process of atrial electrophysiological remodeling. We have documented both significant electrophysiological remodeling 8,9 and biochemical evidence of oxidative stress...

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The effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea‐pig ventricular myocytes

Cited by 56 publications

References 48 publications

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Oxygen, oxidative stress, hypoxia, and heart failure

Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation

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